Tirzepatide

Tirzepatide (as Mounjaro) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. Zepbound is also approved for the treatment of moderate-to-severe obstructive sleep apnea in adults with obesity. and return to their previous weight within a year and a half. == Contraindications ==

Tirzepatide is contraindicated for use in people with a personal or family history of medullary thyroid cancer and people with multiple endocrine neoplasia syndrome type2. == Adverse effects ==

Preclinical, phase I, and phase II clinical trials indicated that tirzepatide exhibits adverse effects similar to those of other established GLP-1 receptor agonists, such as dulaglutide (sold as Trulicity) and semaglutide (sold as Wegovy, Ozempic, and Rybelsus). These effects occur largely in the gastrointestinal tract. The most frequently observed are nausea, diarrhea, and vomiting, which increased in incidence with the dosage amount (that is, the higher the dose, the higher the likelihood of side effects). The number of patients who discontinued taking tirzepatide also increased as the dosage increased, with patients taking 15 mg having a 25% discontinuation rate vs 5.1% for 5-mg patients and 11.1% for dulaglutide. To a slightly lesser extent, patients also reported reduced appetite. A systematic review published in 2024 found that tirzepatide is well tolerated and not associated with pancreatitis, but later case reports have found that pancreatitis followed initiation of treatment with tirzepatide. In 2026, the UK Medicines and Healthcare products Regulatory Agency (MHRA) updated its guidance on GLP-1 medication after an increase in reports to the agency's Yellow Card Scheme of acute pancreatitis, with fatalities, in patients taking semaglutide or tirzepatide, to warn of a small risk of developing severe acute pancreatitis. It has been suggested that suicidal behavior and ideation may be associated with use of GLP-1 RA medication, but studies in several countries since 2024 do not support this. In January 2026, the US Food and Drug Administration requested removal of a suicidal behavior and ideation warning from GLP-1 RA medications. == Pharmacology ==

Tirzepatide is an analog of gastric inhibitory polypeptide (GIP), a human hormone that stimulates the release of insulin from the pancreas. Tirzepatide is a linear polypeptide of 39 amino acids that has been chemically modified by lipidation to improve its uptake into cells and its stability to metabolism. It completed phase III trials globally in 2021. Mechanism of action Tirzepatide has a greater affinity to GIP receptors than to GLP-1 receptors, and this dual agonist behavior has been shown to produce greater reductions of hyperglycemia compared to a selective GLP-1 receptor agonist. Signaling studies reported that tirzepatide mimics the actions of natural GIP at the GIP receptor. At the GLP-1 receptor, though, tirzepatide shows bias toward cAMP (a messenger associated with regulation of glycogen, sugar, and lipid metabolism) generation rather than β-arrestin recruitment. This combination of preference toward GIP receptor and distinct signaling properties at GLP-1 suggest this biased agonism increases insulin secretion. Tirzepatide has been reported to increase levels of adiponectin, an adipokine involved in the regulation of both glucose and lipid metabolism, with a maximum increase of 26% from baseline after 26 weeks, at the 10 mg dosage. == Chemistry ==

Structure Tirzepatide is an analog of the human GIP hormone with a C20 fatty diacid portion attached, used to optimise the uptake and metabolism of the compound. Synthesis The synthesis of tirzepatide was first disclosed in patents filed by Eli Lilly and Company in 2016. This uses standard solid phase peptide synthesis, with an allyloxycarbonyl protecting group on the lysine at position 20 of the linear chain of amino acids, allowing a final set of chemical transformations in which the sidechain amine of that lysine is derivatized with the lipid-containing fragment. Large-scale manufacturing processes have been reported for this compound. == History ==

Eli Lilly and Company first applied for a patent for a method of glycemic control using tirzepatide in 2016. After completing the SURPASS-2 trial (NCT03987919), the company announced in April 2022 that tirzepatide had successfully met its clinical endpoints in obese and overweight participants without diabetes. In industry-funded preliminary trials, tirzepatide showed minor improvement of reductions (2.01%–2.30% depending on dosage) in glycated hemoglobin tests relative to the injected GLP-1 analog semaglutide (1.86%). A 10 mg dose has also been shown to be effective in reducing insulin resistance, with a reduction of around 8% from baseline, measured using HOMA2-IR (computed with fasting insulin). In a phase III double-blind, randomized, controlled trial supported by Eli Lilly, nondiabetic adults with a body mass index of 30 or more, or 27 or more and at least one weight-related complication, excluding diabetes, were randomized to receive once-weekly, subcutaneous tirzepatide (5, 10, or 15 mg) or placebo. The mean percentage change in weight at week 72 was −15.0% (95% confidence interval [CI], −15.9 to −14.2) with 5-mg weekly doses of tirzepatide, −19.5% (95% CI, −20.4 to −18.5) with 10-mg doses, and −20.9% (95% CI, −21.8 to −19.9) with 15-mg doses. Weight change in the placebo group was −3.1% (95% CI, −4.3 to −1.9). The FDA approved tirzepatide based on evidence from nine clinical trials of 7,769 participants with type 2 diabetes, of whom 5,415 received tirzepatide. The trials were conducted at 673 sites in 24 countries, including Argentina, Australia, Brazil, Canada, India, Israel, Japan, Mexico, Russian Federation, South Korea, Taiwan, European Union, and the United States (including Puerto Rico). == Society and culture ==

Legal status The U.S. Food and Drug Administration (FDA) granted the application for tirzepatide priority review designation. Tirzepatide was approved for medical use in the European Union in September 2022. In December 2024, the FDA approved tirzepatide (Zepbound) as the first medication to be used in the treatment of moderate to severe obstructive sleep apnea. The FDA granted the application for tirzepatide (Zepbound) fast track, priority review, and breakthrough therapy designations for the treatment of moderate to severe obstructive sleep apnea. The FDA declared a shortage of tirzepatide in December 2022. It declared the shortage over in October 2024, but enforcement was delayed until the end of 2024, after a lawsuit by compounding pharmacies challenged the declaration. The U.S. National Association of Boards of Pharmacy says there are tens of thousands of online pharmacies operating out of compliance with state and federal regulations or the association's recommendations. The FDA has not evaluated these for safety and effectiveness and they are thus considered not to have been shown to be safe or effective. Rejection of Biden-era proposal On April 4, 2025, the Trump Administration declined to finalize a Biden Administration proposal that would have required Medicare, Medicaid, and CHIP to broadly cover GLP-1s for weight loss. Nevertheless, CMS has said it might cover obesity medication in the future. In November 2025, the Trump Administration announced TrumpRx, an initiative similar to GoodRx to lower the price of GLP-1s to $245 per month for patients covered by Medicaid and CHIP and $50 month for Medicare patients if states opted in. Coverage for patients with obesity and at least one comorbidity (elevated LDL-cholesterol, high blood pressure and/or MASLD) may be implemented as early as April 1, 2026. The cost will be significantly higher because most insurance companies do not cover it in their formulary. Before this change, most Medicaid and CHIP patients paid $3 a month, the same as for brand-name medication. == Research ==

In a phase III trial, tirzepatide demonstrated clinically significant benefits among participants with obesity and heart failure with preserved ejection fraction. Over two years of follow-up, tirzepatide decreased participants' risk of major cardiovascular (CV) complications—a combined endpoint including urgent heart failure visits, hospitalizations, more frequent diuretic treatment, and CV mortality—by 38% compared to a placebo. An observational study on patients with obesity and type 2 diabetes and heart failure with preserved ejection fraction reported that tirzepatide had a lower risk of hospitalization for heart failure and all-cause death combined than sitagliptin. In a 72-week, phase IIIb open-label head-to-head trial of adults with obesity without diabetes, tirzepatide at the maximum tolerated dose produced greater mean weight loss than semaglutide and larger reductions in waist circumference, while gastrointestinal adverse events were the most common with both drugs. A 2024 systematic review found that tirzepatide demonstrates benefits in the management of metabolic dysfunction–associated steatotic liver disease. == References ==